|
1
|
Martín-Sierra C, Bravo MJ, Sáez ME, De Rojas I, Santos M, Martín-Carmona J, Corma-Gómez A, González-Serna A, Royo JL, Pineda JA, Rivero A, Rivero-Juárez A, Macías J, Real LM. The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study). Antiviral Res 2024; 222:105795. [PMID: 38181855 DOI: 10.1016/j.antiviral.2024.105795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/30/2023] [Accepted: 01/02/2024] [Indexed: 01/07/2024]
Abstract
BACKGROUND & AIMS It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). OBJECTIVE To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. PATIENTS AND METHODS In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. RESULTS It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. CONCLUSIONS Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.
Collapse
Affiliation(s)
- Carmen Martín-Sierra
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain
| | - María José Bravo
- Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Universidad de Málaga, Málaga, Spain
| | | | - Itziar De Rojas
- Research Center and Memory Clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain
| | - Marta Santos
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Jesica Martín-Carmona
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Anaïs Corma-Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain
| | - Alejandro González-Serna
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Fisiología. Universidad de Sevilla, Sevilla, Spain
| | - José Luis Royo
- Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Universidad de Málaga, Málaga, Spain
| | - Juan A Pineda
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Medicina. Universidad de Sevilla, Sevilla, Spain
| | - Antonio Rivero
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
| | - Antonio Rivero-Juárez
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBC), Hospital Universitario Reina Sofía de Córdoba, Universidad de Córdoba, Córdoba, Spain
| | - Juan Macías
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Medicina. Universidad de Sevilla, Sevilla, Spain
| | - Luis Miguel Real
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen de Valme /CSIC/Universidad de Sevilla, Sevilla, Spain; Departamento de Bioquímica Médica, Biología Molecular e Inmunología, Universidad de Sevilla, Sevilla, Spain.
| |
Collapse
|
|
2
|
Mambro A, Afshar A, Leone F, Dussault C, Stoové M, Savulescu J, Rich JD, Rowan DH, Sheehan J, Kronfli N. Reimbursing incarcerated individuals for participation in research: A scoping review. THE INTERNATIONAL JOURNAL OF DRUG POLICY 2024; 123:104283. [PMID: 38109837 DOI: 10.1016/j.drugpo.2023.104283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 11/18/2023] [Accepted: 11/29/2023] [Indexed: 12/20/2023]
Abstract
BACKGROUND Little is known about global practices regarding the provision of reimbursement for the participation of people who are incarcerated in research. To determine current practices related to the reimbursement of incarcerated populations for research, we aimed to describe international variations in practice across countries and carceral environments to help inform the development of more consistent and equitable practices. METHODS We conducted a scoping review by searching PubMed, Cochrane library, Medline, and Embase, and conducted a grey literature search for English- and French-language articles published until September 30, 2022. All studies evaluating any carceral-based research were included if recruitment of incarcerated participants occurred inside any non-juvenile carceral setting; we excluded studies if recruitment occurred exclusively following release. Where studies failed to indicate the presence or absence of reimbursement, we assumed none was provided. RESULTS A total of 4,328 unique articles were identified, 2,765 were eligible for full text review, and 426 were included. Of these, 295 (69%) did not offer reimbursement to incarcerated individuals. A minority (n = 13; 4%) included reasons explaining the absence of reimbursement, primarily government-level policies (n = 7). Among the 131 (31%) studies that provided reimbursement, the most common form was monetary compensation (n = 122; 93%); five studies (4%) offered possible reduced sentencing. Reimbursement ranged between $3-610 USD in total and 14 studies (11%) explained the reason behind the reimbursements, primarily researchers' discretion (n = 9). CONCLUSIONS The majority of research conducted to date in carceral settings globally has not reimbursed incarcerated participants. Increased transparency regarding reimbursement (or lack thereof) is needed as part of all carceral research and advocacy efforts are required to change policies prohibiting reimbursement of incarcerated individuals. Future work is needed to co-create international standards for the equitable reimbursement of incarcerated populations in research, incorporating the voices of people with lived and living experience of incarceration.
Collapse
Affiliation(s)
- Andrea Mambro
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Avideh Afshar
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Frederic Leone
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Camille Dussault
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Mark Stoové
- Burnet Institute, School of Public Health and Preventative Medicine, Monash University, Melbourne, Victoria, Australia
| | - Julian Savulescu
- Oxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, United Kingdom; Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Josiah D Rich
- Center for Health and Justice Transformation, The Miriam and Rhode Island Hospitals, Departments of Medicine and Epidemiology, Brown University, Providence, Rhode Island, USA
| | - Daniel H Rowan
- Division of Infectious Disease, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA
| | | | - Nadine Kronfli
- Centre for Outcomes Research and Evaluation, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, Division of Infectious Disease and Chronic Viral Illness Service, McGill University, Montreal, Quebec, Canada.
| |
Collapse
|
|
3
|
Radkowski M, Grabarczyk P, Kryczka T, Caraballo Cortès K, Kubicka-Russel D, Janiak M, Osuch S, Perlejewski K, Laskus T. Cytokine profile and viral diversity in the early seronegative stage of community-acquired hepatitis C virus (HCV) infection. Sci Rep 2023; 13:20045. [PMID: 37973814 PMCID: PMC10654698 DOI: 10.1038/s41598-023-47335-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 11/12/2023] [Indexed: 11/19/2023] Open
Abstract
Most Hepatitis C virus (HCV)-infected subjects develop chronic infection, whereas a minority clear the virus in the early phase of infection. We analyzed factors associated with outcome (chronicity vs clearance) during the preclinical seronegative phase of community-acquired HCV infection. Among 17.5 million blood donations in the years 2000-2016, 124 blood donors were found to be HCV RNA-positive/anti-HCV-negative. All were contacted after 0.5-12.7 years and 40 responded and provided blood sample. Hypervariable region 1 was analyzed by ultradeep pyrosequencing and cytokines in serum were quantified by Luminex (R&D Systems) multiplex immunoassay. Twenty-one (52.5%) donors were found to be HCV-RNA-positive, while 19 (47.5%) were HCV RNA negative (none received antiviral treatment). All but one seroconverted to anti-HCV. Donors with resolving hepatitis did not differ significantly from donors with chronic infection with respect to age, genotypes, IL28B polymorphisms, number of viral variants, nucleotide diversity per site or the overall number of nucleotide substitutions. However, the former group had significantly higher levels of IL-1beta, IL-1RA, IL-6, IFN-gamma and FGF-2 in serum. In our study of community-acquired acute hepatitis C approximately half of all subjects eliminated the virus spontaneously, and this clearance was associated with marked cytokine response in the early seronegative stage of infection.
Collapse
Affiliation(s)
- Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Piotr Grabarczyk
- Department of Virology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Tomasz Kryczka
- Department of Development of Nursing and Social and Medical Sciences, Medical University of Warsaw, Warsaw, Poland
| | - Kamila Caraballo Cortès
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Dorota Kubicka-Russel
- Department of Virology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Maciej Janiak
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Sylwia Osuch
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Karol Perlejewski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Tomasz Laskus
- Department of Adult Infectious Diseases, Medical University of Warsaw, 37 Wolska St., 01-201, Warsaw, Poland.
| |
Collapse
|
|
4
|
Gömer A, Delarocque J, Puff C, Nocke MK, Reinecke B, Baumgärtner W, Cavalleri JMV, Feige K, Steinmann E, Todt D. Dose-Dependent Hepacivirus Infection Reveals Linkage between Infectious Dose and Immune Response. Microbiol Spectr 2022; 10:e0168622. [PMID: 35993785 PMCID: PMC9602444 DOI: 10.1128/spectrum.01686-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/03/2022] [Indexed: 12/31/2022] Open
Abstract
More than 70 million people worldwide are still infected with the hepatitis C virus 30 years after its discovery, underscoring the need for a vaccine. To develop an effective prophylactic vaccine, detailed knowledge of the correlates of protection and an immunocompetent surrogate model are needed. In this study, we describe the minimum dose required for robust equine hepacivirus (EqHV) infection in equids and examined how this relates to duration of infection, seroconversion, and transcriptomic responses. To investigate mechanisms of hepaciviral persistence, immune response, and immune-mediated pathology, we inoculated eight EqHV naive horses with doses ranging from 1-2 copies to 1.3 × 106 RNA copies per inoculation. We characterized infection kinetics, pathology, and transcriptomic responses via next generation sequencing. The minimal infectious dose of EqHV in horses was estimated at 13 RNA copies, whereas 6 to 7 copies were insufficient to cause infection. Peak viremia did not correlate with infectious dose, while seroconversion and duration of infection appeared to be affected. Notably, seroconversion was undetectable in the low-dose infections within the surveillance period (40 to 50 days). In addition, transcriptomic analysis revealed a nearly dose-dependent effect, with greater immune activation and inflammatory response observed in high-dose infections than in low-dose infections. Interestingly, inoculation with 6-7 copies of RNA that did not result in productive infection, but was associated with a strong immune response, similar to that observed in the high-dose infections. IMPORTANCE We demonstrate that the EqHV dose of infection plays an important role for inducing immune responses, possibly linked to early clearance in high-dose and prolonged viremia in low-dose infections. In particular, pathways associated with innate and adaptive immune responses, as well as inflammatory responses, were more strongly upregulated in high-dose infections than in lower doses. Hence, inoculation with low doses may enable EqHV to evade strong immune responses in the early phase and therefore promote robust, long-lasting infection.
Collapse
Affiliation(s)
- André Gömer
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Institute of Virology, University of Veterinary Medicine Hannover, Hanover, Germany
| | - Julien Delarocque
- Clinic for Horses, University of Veterinary Medicine Hannover, Hanover, Germany
| | - Christina Puff
- Department of Pathology, University of Veterinary Medicine Hannover, Hanover, Germany
| | - Maximilian K. Nocke
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Birthe Reinecke
- Institute of Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Hanover, Germany
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine Hannover, Hanover, Germany
| | - Jessika M. V. Cavalleri
- Clinical Section of Equine Internal Medicine, Department of Companion Animals and Horses, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Karsten Feige
- Clinic for Horses, University of Veterinary Medicine Hannover, Hanover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- European Virus Bioinformatics Center (EVBC), Jena, Germany
| |
Collapse
|
|
5
|
Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial. Viruses 2021; 13:v13071351. [PMID: 34372558 PMCID: PMC8310243 DOI: 10.3390/v13071351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/03/2021] [Accepted: 07/08/2021] [Indexed: 11/17/2022] Open
Abstract
Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.
Collapse
|
|
6
|
Cox A, Sulkowski M, Sugarman J. Ethical and Practical Issues Associated With the Possibility of Using Controlled Human Infection Trials in Developing a Hepatitis C Virus Vaccine. Clin Infect Dis 2020; 71:2986-2990. [PMID: 32442262 PMCID: PMC7778335 DOI: 10.1093/cid/ciaa640] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 05/21/2020] [Indexed: 01/15/2023] Open
Abstract
Despite the existence of established treatments for hepatitis C virus (HCV), more effective means of preventing infection, such as a vaccine, are arguably needed to help reduce substantial global morbidity and mortality. Given the expected challenges of developing such a vaccine among those at heightened risk of infection, controlled human infection studies seem to be a promising potential approach to HCV vaccine development, but they raise substantial ethical and practical concerns. In this article, we describe some of the challenges related to the possibility of using controlled human infection studies to accelerate HCV vaccine development. The related ethical and practical concerns require further deliberation before such studies are planned and implemented.
Collapse
Affiliation(s)
- Andrea Cox
- School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
| | - Mark Sulkowski
- School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Jeremy Sugarman
- School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA
- Berman Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland, USA
| |
Collapse
|
|
7
|
Mekonnen ZA, Masavuli MG, Yu W, Gummow J, Whelan DM, Al-Delfi Z, Torresi J, Gowans EJ, Grubor-Bauk B. Enhanced T Cell Responses Induced by a Necrotic Dendritic Cell Vaccine, Expressing HCV NS3. Front Microbiol 2020; 11:559105. [PMID: 33343515 PMCID: PMC7739890 DOI: 10.3389/fmicb.2020.559105] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/28/2020] [Indexed: 12/21/2022] Open
Abstract
A vaccine that induces potent, broad and sustained cell-mediated immunity, resulting in effective memory has the potential to restrict hepatitis C (HCV) virus infection. Early, multi-functional CD4+ and CD8+ T cell responses against non-structural protein 3 (NS3) have been associated with HCV clearance. Necrotic cells generate strong immune responses and represent a major antigenic source used by dendritic cells (DC) for processing and presentation, but there is conflicting evidence as to their immunogenicity in vaccination. Immunization with DC loaded with viral antigens has been done in the past, but to date the immunogenicity of live vs. necrotic DC vaccines has not been investigated. We developed a DC2.4 cell line stably expressing HCV NS3, and compared the NS3-specific responses of live vs. necrotic NS3 DC. Vaccination of mice with necrotic NS3 DC increased the breadth of T-cell responses and enhanced the production of IL-2, TNF-α, and IFN-γ by effector memory CD4+ and CD8+T cells, compared to mice vaccinated with live NS3 DC. A single dose of necrotic NS3 DC vaccine induced a greater influx and activation of cross-presenting CD11c+ CD8α+ DC and necrosis-sensing Clec9A+ DC in the draining lymph nodes. Furthermore, using a hydrodynamic challenge model necrotic NS3 DC vaccination resulted in enhanced clearance of NS3-positive hepatocytes from the livers of vaccinated mice. Taken together, the data demonstrate that necrotic DC represent a novel and exciting vaccination strategy capable of inducing broad and multifunctional T cell memory.
Collapse
Affiliation(s)
- Zelalem A Mekonnen
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Makutiro G Masavuli
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Wenbo Yu
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia.,Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Jason Gummow
- Gene Silencing and Expression Laboratory, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Dawn M Whelan
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Zahraa Al-Delfi
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
| | - Eric J Gowans
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| | - Branka Grubor-Bauk
- Viral Immunology Group, Discipline of Surgery, Basil Hetzel Institute for Translational Medicine, University of Adelaide, Adelaide, SA, Australia
| |
Collapse
|
|
8
|
Duncan JD, Urbanowicz RA, Tarr AW, Ball JK. Hepatitis C Virus Vaccine: Challenges and Prospects. Vaccines (Basel) 2020; 8:vaccines8010090. [PMID: 32079254 PMCID: PMC7157504 DOI: 10.3390/vaccines8010090] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/25/2020] [Accepted: 02/04/2020] [Indexed: 02/07/2023] Open
Abstract
The hepatitis C virus (HCV) causes both acute and chronic infection and continues to be a global problem despite advances in antiviral therapeutics. Current treatments fail to prevent reinfection and remain expensive, limiting their use to developed countries, and the asymptomatic nature of acute infection can result in individuals not receiving treatment and unknowingly spreading HCV. A prophylactic vaccine is therefore needed to control this virus. Thirty years since the discovery of HCV, there have been major gains in understanding the molecular biology and elucidating the immunological mechanisms that underpin spontaneous viral clearance, aiding rational vaccine design. This review discusses the challenges facing HCV vaccine design and the most recent and promising candidates being investigated.
Collapse
Affiliation(s)
- Joshua D. Duncan
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
- Correspondence:
| | - Richard A. Urbanowicz
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Alexander W. Tarr
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| | - Jonathan K. Ball
- School of Life Sciences, The University of Nottingham, Nottingham NG7 2UH, UK; (R.A.U.); (A.W.T.); (J.K.B.)
- NIHR Nottingham BRC, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham NG7 2UH, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| |
Collapse
|
|
9
|
Kimble MM, Javanbakht M, Chew KW, Stafylis C, He D, Ramirez S, Baik Y, Saab S, Klausner JD. Sociodemographic and clinical characteristics of persons who experienced spontaneous hepatitis C viral clearance. BMC Infect Dis 2019; 19:626. [PMID: 31307403 PMCID: PMC6632203 DOI: 10.1186/s12879-019-4223-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 06/26/2019] [Indexed: 11/13/2022] Open
Abstract
Background In the United States Hepatitis C virus (HCV) viral clearance is estimated to range between 20 and 30%. The objective of this study was to estimate the frequency of HCV clearance and identify correlates of viral clearance among patients newly identified as HCV antibody positive in a large urban health system in Los Angeles, California. Methods We identified patients between November 2015 and September 2017 as part of a newly implemented HCV screening and linkage-to-care program at University of California Los Angeles (UCLA) Health System. All patients were eligible for screening, though there were additional efforts to screen patients born between 1945 and 1965. We reviewed Medical records to categorize anti-HCV antibody positive patients as having spontaneously cleared HCV infection (HCV RNA not detected) or not (HCV RNA detected). We excluded those with a prior history of anti-HCV positivity or history of HCV treatment. We compared differences between those with and without detectable HCV RNA using chi-square test, Fisher’s exact test, and t-test as appropriate. We assessed factors associated with HCV clearance using logistic regression analysis. Results Among the 320 patients included in this study, 56% were male. Baby boomers (52–72 years of age) comprised the single largest age group (62%). We found spontaneous HCV clearance in 58% (n = 185). HCV viral clearance was slightly higher among women as compared to men (63% vs. 53%; p value = 0.07) and varied by race/ethnicity: clearance among Blacks/African Americans was 37% vs. 58% among whites (p value = 0.02). After adjusting for age, race/ethnicity, and sex we found that those diagnosed with chronic kidney disease had a tendency of decreased HCV viral clearance (adjusted OR = 0.34; 95% CI 0.14–1.03). Conclusion Of those patients newly identified as anti-HCV positive, 58% had cleared HCV virus, while the rest showed evidence of active infection. In addition, we found that clearance varied by race/ethnicity and clinical characteristics.
Collapse
Affiliation(s)
- Mabel Michille Kimble
- Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, 10920 Wilshire Blvd. Suite 350 Room 40, Los Angeles, CA, 90024, USA
| | - Marjan Javanbakht
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, USA
| | - Kara W Chew
- Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, 10920 Wilshire Blvd. Suite 350 Room 40, Los Angeles, CA, 90024, USA
| | - Chrysovalantis Stafylis
- Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, 10920 Wilshire Blvd. Suite 350 Room 40, Los Angeles, CA, 90024, USA.
| | - Di He
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, USA
| | - Samantha Ramirez
- Department of Medicine and Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA
| | - Yeonsoo Baik
- Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, USA
| | - Sammy Saab
- Department of Medicine and Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, USA
| | - Jeffrey D Klausner
- Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, 10920 Wilshire Blvd. Suite 350 Room 40, Los Angeles, CA, 90024, USA.,Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, Los Angeles, USA
| |
Collapse
|
|
10
|
Casey JL, Feld JJ, MacParland SA. Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection. Cells 2019; 8:cells8040317. [PMID: 30959825 PMCID: PMC6523849 DOI: 10.3390/cells8040317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022] Open
Abstract
Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.
Collapse
Affiliation(s)
- Julia L Casey
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Jordan J Feld
- Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada.
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
| | - Sonya A MacParland
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 2C4, Canada.
- Departments of Laboratory Medicine & Pathobiology and Immunology, University of Toronto, Toronto, ON M5S 1A1, Canada.
| |
Collapse
|
|
11
|
Irshad M, Gupta P, Irshad K. Immunopathogenesis of Liver Injury During Hepatitis C Virus Infection. Viral Immunol 2019; 32:112-120. [PMID: 30817236 DOI: 10.1089/vim.2018.0124] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The present report describes current concepts about the mechanism of liver cell injury caused by host immune response against hepatitis C virus (HCV) infection in human beings. This report is based on the observations from experimental studies and follow-up actions on human liver diseases. The results from different investigations suggest that liver injury depends on the presentation of viral antigen and the level of host immune response raised against HCV-related peptides. Both innate and adaptive immunity are triggered to counter the viral onset. During development of host immunity, the cell-mediated immune response involving CD4+ Th1 cells and CD8+ cytotoxic T-lymphocyte (CTL) cells were found to play a major role in causing liver damage. The hepatic Innate lymphoid cells (ILCs) subsets are involved in the immune regulation of different liver diseases: viral hepatitis, mechanical liver injury, and fibrosis. Humoral immunity and natural killer (NK) cell action also contributed in liver cell injury by antibody-dependent cellular cytotoxicity (ADCC). In fact, immunopathogenesis of HCV infection is a complex phenomenon where regulation of immune response at several steps decides the possibility of viral elimination or persistence. Regulation of immune response was noted starting from viral-host interaction to immune reaction cascade engaged in cell damage. The activation or suppression of interferon-stimulated genes, NK cell action, CTL inducement by regulatory T cells (Treg), B cell proliferation, and so on was demonstrated during HCV infection. Involvement of HLA in antigen presentation, as well as types of viral genotypes, also influenced host immune response against HCV peptides. The combined effect of all these effector mechanisms ultimately decides the progression of viral onset to acute or chronic infection. In conclusion, immunopathogenesis of liver injury after HCV infection may be ascribed mainly to host immune response. Second, it is cell-mediated immunity that plays a predominant role in liver cell damage.
Collapse
Affiliation(s)
- Mohammad Irshad
- 1 Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Priyanka Gupta
- 2 Clinical Biochemistry Division, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Khushboo Irshad
- 3 Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
12
|
Peng H, Zhang L, Feng Y, Tang H, Luo Z, Qi Z, Xia X, Zhao P. A cross-sectional serum investigation of a clustering hepatitis C virus infection in Southwest China. J Med Virol 2018; 91:508-513. [PMID: 30204254 DOI: 10.1002/jmv.25315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 09/03/2018] [Indexed: 11/09/2022]
Abstract
Serum samples were collected in a village with a clustering hepatitis C virus (HCV) infection. HCV antibody, HCV RNA loads, liver function indexes, HCV envelope antibody, and neutralizing activity were assessed. Among 851 adult sera, 342 samples were positive for anti-HCV. Of these positive samples, 254 (74.3%) were HCV RNA positive (≥800 copies/mL). None of the 69 children's sera were positive for HCV antibody or RNA. Among the HCV antibody positive sera, alanine aminotransferase, and aspartate aminotransferase levels increased with the higher virus loads, but decreased when virus loads were higher than 1 × 10 6 copies/mL. HCV envelope antibody and neutralizing antibody levels increased with viral load.
Collapse
Affiliation(s)
- Haoran Peng
- Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Longyan Zhang
- Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Yue Feng
- Molecular Virology Laboratory, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Hailin Tang
- Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Zhenghan Luo
- Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Zhongtian Qi
- Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| | - Xueshan Xia
- Molecular Virology Laboratory, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Ping Zhao
- Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, China
| |
Collapse
|
|
13
|
Sacks-Davis R, Pedrana AE, Scott N, Doyle JS, Hellard ME. Eliminating HIV/HCV co-infection in gay and bisexual men: is it achievable through scaling up treatment? Expert Rev Anti Infect Ther 2018; 16:411-422. [PMID: 29722275 DOI: 10.1080/14787210.2018.1471355] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Broad availability of direct-acting antiviral therapy for hepatitis C virus (HCV) raises the possibility that HCV prevalence and incidence can be reduced through scaling-up treatment, leading to the elimination of HCV. High rates of linkage to HIV care among HIV-infected gay and bisexual men may facilitate high uptake of HCV treatment, possibly making HCV elimination more achievable in this group. Areas covered: This review covers HCV elimination in HIV-infected gay and bisexual men, including epidemiology, spontaneous clearance and long term sequelae in the absence of direct-acting antiviral therapy; direct-acting antiviral therapy uptake and effectiveness in this group; HCV reinfection following successful treatment; and areas for further research. Expert commentary: Early data from the direct-acting antiviral era suggest that treatment uptake is increasing among HIV infected GBM, and SVR rates are very promising. However, in order to sustain current treatment rates, additional interventions at the behavioral, physician, and structural levels may be required to increase HCV diagnosis, including prompt detection of HCV reinfection. Timely consideration of these issues is required to maximize the population-level impact of HCV direct-acting antiviral therapy. Potential HCV transmissions from HIV-uninfected GBM, across international borders, and from those who are not GBM also warrant consideration.
Collapse
Affiliation(s)
- Rachel Sacks-Davis
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,b Department of Medicine , University of Melbourne , Parkville , Australia
| | - Alisa E Pedrana
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,c Department of Epidemiology and Preventive Medicine , Monash University , Melbourne , Australia
| | - Nick Scott
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,c Department of Epidemiology and Preventive Medicine , Monash University , Melbourne , Australia
| | - Joseph S Doyle
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,d Central Clinical School , Monash University , Melbourne , Australia
| | - Margaret E Hellard
- a Disease Elimination Program , Burnet Institute , Melbourne , Australia.,c Department of Epidemiology and Preventive Medicine , Monash University , Melbourne , Australia
| |
Collapse
|
|
14
|
Shawa IT, Felmlee DJ, Hegazy D, Sheridan DA, Cramp ME. Exploration of potential mechanisms of hepatitis C virus resistance in exposed uninfected intravenous drug users. J Viral Hepat 2017; 24:1082-1088. [PMID: 28475247 DOI: 10.1111/jvh.12720] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/27/2017] [Indexed: 12/14/2022]
Abstract
A rare outcome following exposure to hepatitis C virus (HCV) is a lack of observable infection as clinically measured by HCV RNA- or HCV-recognizing antibodies. The population who exhibit this trait is termed exposed uninfected (EU). Increasing evidence has refined characterization of these individuals, distinct from those who become infected but spontaneously clear HCV. Study of the EU population is highly pertinent for the discovery of antiviral mechanisms of resistance that can reveal antiviral therapeutic strategies. This review provides an overview of similarities and differences of the EU population relative to spontaneous resolvers and the majority whom develop chronic HCV infection, and focusses on possible mechanisms of resistance including innate and adaptive immunity, genetics and lipid interactions.
Collapse
Affiliation(s)
- I T Shawa
- Hepatology Research Group, Institute of Translational and Stratified Medicine, , Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - D J Felmlee
- Hepatology Research Group, Institute of Translational and Stratified Medicine, , Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - D Hegazy
- Hepatology Research Group, Institute of Translational and Stratified Medicine, , Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - D A Sheridan
- Hepatology Research Group, Institute of Translational and Stratified Medicine, , Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| | - M E Cramp
- Hepatology Research Group, Institute of Translational and Stratified Medicine, , Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK
| |
Collapse
|
|
15
|
Xiong H, Rong X, Wang M, Xu R, Huang K, Liao Q, Huang J, Chen J, Li C, Tang X, Shan Z, Zhang M, Nelson K, Fu Y. HBV/HCV co-infection is associated with a high level of HCV spontaneous clearance among drug users and blood donors in China. J Viral Hepat 2017; 24:312-319. [PMID: 27943542 DOI: 10.1111/jvh.12644] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 09/20/2016] [Indexed: 12/11/2022]
Abstract
Understanding the biology of spontaneous clearance of hepatitis C virus (HCV) infection could lead to improved strategies to prevent the sequelae associated with chronic HCV infection. Chronic infections with hepatitis virus are very common in China, but the factors associated with spontaneous clearance of HCV have not been adequately studied. We evaluated the spontaneous clearance of HCV among 1918 drug users and 1526 HCV-seropositive blood donors in Guangzhou, China. Among participants who were co-infected with hepatitis B virus (HBV), 41.38% of drug users and 39.47% of blood donors had cleared their HCV infection without antiviral therapy compared to 9.41% of drug users and 16.73% of blood donors who were mono-infected with a single virus (P<.01). The proportion of subjects who had cleared their HCV infection was significantly greater in the co-infected subjects whose serum HBV DNA was greater than 2000IU/mL than those with lower levels. A multiple logistic regression analysis found female gender, IL28B rs8099917 TT genotype, HBV co-infection and blood donors (vs drug users) associated with increased spontaneous clearance of HCV infection. Although acute HCV infections are common in China, the incidence of chronic HCV may be reduced among the high prevalence of chronic HBV and IL28B genotypes associated with spontaneous clearance of HCV in Chinese populations.
Collapse
Affiliation(s)
- H Xiong
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - X Rong
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - M Wang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - R Xu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - K Huang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - Q Liao
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - J Huang
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - J Chen
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - C Li
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - X Tang
- Department of Transfusion Medicine, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Z Shan
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| | - M Zhang
- Faculty of Infectious Diseases, Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, USA
| | - K Nelson
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Y Fu
- Guangzhou Blood Center, Guangzhou, Guangdong, China
- The Key Medical Disciplines and Specialties Program of Guangzhou, Guangdong, China
| |
Collapse
|
|
16
|
Boisvert M, Shoukry NH. Type III Interferons in Hepatitis C Virus Infection. Front Immunol 2016; 7:628. [PMID: 28066437 PMCID: PMC5179541 DOI: 10.3389/fimmu.2016.00628] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 12/08/2016] [Indexed: 12/20/2022] Open
Abstract
The interferon (IFN)-λ family of type III cytokines includes the closely related interleukin (IL)-28A (IFN-λ2), IL-28B (IFN-λ3), and IL-29 (IFN-λ1). They signal through the Janus kinases (JAK)-signal transducers and activators of transcription pathway and promote an antiviral state by the induction of expression of several interferon-stimulated genes (ISGs). Contrary to type I IFNs, the effect of IFN-λ cytokines is largely limited to epithelial cells due to the restricted pattern of expression of their specific receptor. Several genome-wide association studies have established a strong correlation between polymorphism in the region of IL-28B gene (encoding for IFN-λ3) and both spontaneous and therapeutic IFN-mediated clearance of hepatitis C virus (HCV) infection, but the mechanism(s) underlying this enhanced viral clearance are not fully understood. IFN-λ3 directly inhibits HCV replication, and in vitro studies suggest that polymorphism in the IFN-λ3 and its recently identified overlapping IFN-λ4 govern the pattern of ISGs induced upon HCV infection of hepatocytes. IFN-λ can also be produced by dendritic cells, and apart from its antiviral action on hepatocytes, it can regulate the inflammatory response of monocytes/macrophages, thus acting at the interface between innate and adaptive immunity. Here, we review the current state of knowledge about the role of IFN-λ cytokines in mediating and regulating the immune response during acute and chronic HCV infections.
Collapse
Affiliation(s)
- Maude Boisvert
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) , Montréal, QC , Canada
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada; Département de médecine, Université de Montréal, Montréal, QC, Canada
| |
Collapse
|
|
17
|
Boisvert M, Zhang W, Elrod EJ, Bernard NF, Villeneuve JP, Bruneau J, Marcotrigiano J, Shoukry NH, Grakoui A. Novel E2 Glycoprotein Tetramer Detects Hepatitis C Virus-Specific Memory B Cells. THE JOURNAL OF IMMUNOLOGY 2016; 197:4848-4858. [PMID: 27849172 DOI: 10.4049/jimmunol.1600763] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 10/13/2016] [Indexed: 01/16/2023]
Abstract
Acute hepatitis C virus (HCV) infection culminates in viral persistence in the majority of cases. Abs that recognize the envelope glycoproteins E1 and E2 are generated during the late stages of acute infection, yet their contribution to spontaneous viral clearance remains controversial. Investigation of the humoral responses during acute HCV infection have been limited by the inability to directly identify and characterize HCV-specific B cells. In this study we describe the development of a novel tetramer of the E2 glycoprotein ectodomain (J6, genotype 2a strain), which allowed us to visualize E2-specific B cells longitudinally in the peripheral blood of HCV-infected individuals. HCV-specific class-switched memory B cells were detected in 3 out of 7 participants during late acute infection, with a mean frequency of 0.63% for positive samples (range 0.16-0.67%) and in 7 out of 7 participants with chronic infection with a mean frequency of 0.47% (range 0.20-0.78%). In a cross-sectional study, E2 tetramer positive population was detected in 28 out of 31 chronically infected individuals. Deep sequencing of the BCR from E2-specific class-switched memory B cells sorted from two independent participants revealed a focused repertoire suggestive of clonal selection. Tetramer-specific B cells exhibited skewed CDR3 length distribution and increased mutation frequency compared with naive B cells. This BCR profile is indicative of clonal expansion and affinity maturation. E2 tetramer allows for specific and sensitive ex vivo characterization of rare HCV-specific B cells in infected individuals, and will enable researchers to gain a better understanding of humoral immunity in HCV infection.
Collapse
Affiliation(s)
- Maude Boisvert
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada
| | - Wanrui Zhang
- Yerkes National Primate Research Center, Emory Vaccine Center, Atlanta, GA 30329
| | - Elizabeth J Elrod
- Yerkes National Primate Research Center, Emory Vaccine Center, Atlanta, GA 30329
| | - Nicole F Bernard
- Research Institute of the McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.,Division of Experimental Medicine, McGill University, Montreal, Quebec H3A 1A3, Canada
| | - Jean-Pierre Villeneuve
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada.,Département de Médecine, Faculté de Médecine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada.,Département de Médecine Familiale et de Médecine D'Urgence, Faculté de Médecine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada
| | - Joseph Marcotrigiano
- Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854; and
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec H2X 0A9, Canada; .,Département de Médecine, Faculté de Médecine, Université de Montréal, Montreal, Quebec H3T 1J4, Canada
| | - Arash Grakoui
- Yerkes National Primate Research Center, Emory Vaccine Center, Atlanta, GA 30329; .,Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30329
| |
Collapse
|
|
18
|
Seronegative and occult hepatitis C virus infections in patients with hematological disorders. Arch Virol 2016; 162:63-69. [PMID: 27665588 DOI: 10.1007/s00705-016-3049-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 09/03/2016] [Indexed: 12/20/2022]
Abstract
Studies of the association between seronegative or occult (OCI) hepatitis C virus (HCV) infection, and hematological disorders have yielded controversial results. The aim of this study was to investigate seronegative and OCI HCV infections in among patients with different hematological disorders. This study included 90 anti-HCV-negative patients with either benign or malignant hematological disorders (group I), along with 20 age- and sex-matched apparently healthy subjects, who served as controls (group II). We tested for HCV RNA in sera and PBMCs by RT-nested PCR and for liver enzyme activity. Seronegativity and OCI were detected in 66.7 % and 20 % respectively, of the studied cases (group I). OCI was more evident in Hodgkin lymphoma and thalassemia. A significant increase in AST activity was observed in the seronegative and OCI groups and in ALT and AST in HCV-seronegative or OCI and negative HCV patients (p ≤ 0.05). Seronegativity and OCI are a significant clinical problem in patients with hematological disorders, warranting wider use of molecular tests combined with periodic evaluations of liver functions for diagnostic purposes.
Collapse
|
|
19
|
Abdelwahab SF. Cellular immune response to hepatitis-C-virus in subjects without viremia or seroconversion: is it important? Infect Agent Cancer 2016; 11:23. [PMID: 27186234 PMCID: PMC4867533 DOI: 10.1186/s13027-016-0070-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 03/30/2016] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C Virus (HCV) causes chronic infection and represents a global health burden. To date, there is no licensed vaccine for HCV. The high viral replication rate and the existence of several HCV genotypes and quasispecies hamper the development of an effective universal vaccine. In this regard, the current HCV vaccine candidates show genotype-specific protection or narrow cross reactivity against other genotypes. Importantly, HCV spontaneous clearance occurs in 15-50 % of infected subjects, indicating that natural resistance to chronic infection exists. This phenomenon was demonstrated among humans and chimpanzees and continues to motivate researchers attempting to develop an effective HCV vaccine. However, what constitutes a protective immune response or correlate of protection against HCV infection is still vague. Additionally, the mechanisms behind successful HCV clearance suggest the coordination of several arms of the immune system, with cell-mediated immunity (CMI) playing a crucial role in this process. By contrast, although neutralizing antibodies have been identified, they are isolate-specific and poorly correlate with viral clearance. Antigen-specific CD4 T cells, instead, correlate with transient decline in HCV viremia and long-lasting control of the infection. Unfortunately, HCV has been very successful in evading host immune mechanisms, leading to complications such as liver fibrosis, cirrhosis and hepatocellular carcinoma. Interestingly, CMI to HCV antigens were shown among exposed individuals without viremia or seroconversion, suggesting the clearance of prior HCV infection(s). These individuals include family members living with HCV-infected subjects, healthcare workers, IV drug users, and sexual contacts. The correlates of protection could be closely monitored among these individuals. This review provides a summary of HCV-specific immune responses in general and of CMI in particular in these cohorts. The importance of these CMI responses are discussed.
Collapse
Affiliation(s)
- Sayed F. Abdelwahab
- />Departement of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, 61511 Egypt
- />Department of Microbiology, College of Pharmacy, Taif University, Taif, 21974 Kingdom of Saudi Arabia
| |
Collapse
|
|
20
|
Tsertsvadze T, Sharvadze L, Chkhartishvili N, Dzigua L, Karchava M, Gatserelia L, Abutidze A, Nelson KE. The natural history of recent hepatitis C virus infection among blood donors and injection drug users in the country of Georgia. Virol J 2016; 13:22. [PMID: 26843145 PMCID: PMC4739321 DOI: 10.1186/s12985-016-0478-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 01/27/2016] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatitis C virus (HCV) infection is a serious health problem in Georgia. Methods We conducted a prospective study to identify and characterize the natural history of recent HCV infection since very first days of infection. Recent HCV infection was defined as detectable plasma HCV RNA in the absence of anti-HCV antibodies. Results A total of 7600 HCV seronegative blood donors and 3600 HCV seronegative drug users were screened for recent HCV infection. Among them 7 (0.09 %) blood donors and 10 (0.28 %) drug users tested positive for HCV RNA and were classified as having recent HCV infection. Of these 17 patients 4 (23.5 %) spontaneously cleared the virus by the end of 24 week follow-up. Five clinical forms of recent HCV infection were identified during the follow-up. Four patients had symptomatic disease, including 3 patients with jaundice and other clinical symptoms (2 of them cleared virus) and 1 patient only had other symptoms without jaundice. All symptomatic patients had ALT elevation. Three distinct variants of asymptomatic disease were identified in 13 patients: 9 patients had ALT elevation and none cleared the virus; 2 patients developed chronic disease without ALT elevation; 2 patients cleared virus without anti-HCV seroconversion and without ALT elevation; this form can be described as transitory HCV viremia. Conclusion Additional studies are needed to define clinical and public health implications of transitory HCV viremia. Our study suggests the need for implementing nucleic acid testing of blood donors and key populations in order to more effectively identify HCV infected persons.
Collapse
Affiliation(s)
- Tengiz Tsertsvadze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Lali Sharvadze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Nikoloz Chkhartishvili
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Lela Dzigua
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Marine Karchava
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Lana Gatserelia
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Akaki Abutidze
- Infectious Diseases, AIDS and Clinical Immunology Research Center, 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia. .,Georgian-French Joint Hepatology Clinic 'Hepa', 16 Al. Kazbegi Avenue, Tbilisi, 0160, Georgia.
| | - Kenrad E Nelson
- Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Room E7638, Baltimore, Maryland, 21205, USA.
| |
Collapse
|
|
21
|
de Almeida JPS, Liberatti LS, Barros FEN, Kallaur AP, Lozovoy MAB, Scavuzzi BM, Panis C, Reiche EMV, Dichi I, Simão ANC. Profile of oxidative stress markers is dependent on vitamin D levels in patients with chronic hepatitis C. Nutrition 2015; 32:362-7. [PMID: 26847403 DOI: 10.1016/j.nut.2015.09.016] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 09/09/2015] [Accepted: 09/18/2015] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Although vitamin D deficiency can change liver injury progression in patients with hepatitis C virus (HCV), the main molecular mechanisms involved are largely unknown. The first aim of this study was to evaluate the association between oxidative stress and hypovitaminosis D in patients with HCV. The second aim was to verify whether oxidative stress is involved in the molecular mechanisms related to liver injury. METHODS The study included 147 participants: 89 controls and 58 patients with HCV (vitamin D < 30, n = 32; vitamin D > 30, n = 26). RESULTS Patients with HCV and hypovitaminosis D presented significantly higher aminotransferase-to-platelet ratio index (APRI; P = 0.0464) and viral load (P = 0.0426) levels than patients with HCV without hypovitaminosis D. Regarding oxidative stress, HCV patients with hypovitaminosis D had higher advanced oxidation protein products (P = 0.0409), nitric oxide metabolites (P = 0.0206) levels, and oxidative stress index (P = 0.0196), whereas total radical-trapping antioxidant parameter (P = 0.0446) levels were significantly lower than HCV patients without hypovitaminosis D. Vitamin D in patients with HCV showed inverse correlations with levels of iron (r = -0.407, P = 0.0285), ferritin (r = -0.383, P = 0.0444), APRI (r = -0.453, P = 0.0154) and plasma lipid hydroperoxides levels (r = -0.426, P = 0.0189). CONCLUSION Vitamin D insufficiency contributes to the inflammatory process and oxidative stress imbalance in patients with HCV. The profile of oxidative stress markers in these patients depends on vitamin D levels, which probably change intracellular signalling pathways and increase inflammation and liver injury.
Collapse
Affiliation(s)
- Jorge P Sales de Almeida
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, University of Londrina, Paraná, Brazil
| | - Lucas Silva Liberatti
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, University of Londrina, Paraná, Brazil
| | | | - Ana Paula Kallaur
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, University of Londrina, Paraná, Brazil
| | - Marcell A Batisti Lozovoy
- Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, University of Londrina, Paraná, Brazil
| | | | - Carolina Panis
- Department of Internal Medicine, Health Sciences Center, University of Londrina, Paraná, Brazil
| | - Edna Maria V Reiche
- Department of Internal Medicine, Health Sciences Center, University of Londrina, Paraná, Brazil
| | - Isaias Dichi
- Department of Internal Medicine, Health Sciences Center, University of Londrina, Paraná, Brazil
| | - Andréa Name Colado Simão
- Department of Pathology, Clinical Analysis and Toxicology, University of Londrina, Paraná, Brazil.
| |
Collapse
|
|
22
|
Rezaee-Zavareh MS, Hadi R, Karimi-Sari H, Hossein Khosravi M, Ajudani R, Dolatimehr F, Ramezani-Binabaj M, Miri SM, Alavian SM. Occult HCV Infection: The Current State of Knowledge. IRANIAN RED CRESCENT MEDICAL JOURNAL 2015; 17:e34181. [PMID: 26734487 PMCID: PMC4698335 DOI: 10.5812/ircmj.34181] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 11/02/2015] [Indexed: 12/12/2022]
Abstract
CONTEXT Occult HCV infection (OCI) is defined as the presence of HCV-RNA in hepatocytes and the absence of HCV in the serum according to usual tests. We aimed to define OCI and provide information about the currently available diagnostic methods. Then we focus on specific groups that are at high risk of OCI and finally investigate immune responses to OCI and the available treatment approaches. EVIDENCE ACQUISITION PubMed, Scopus and Google Scholar were comprehensively searched with combination of following keywords: "occult", "hepatitis C virus" and "occult HCV infection". The definition of OCI, diagnostic methods, specific groups that are at high risk and available treatment approaches were extract from literature. An analysis of available articles on OCI also was done based on Scopus search results. RESULTS OCI has been reported in several high-risk groups, especially in hemodialysis patients and subjects with cryptogenic liver disease. Furthermore, some studies have proposed a specific immune response for OCI in comparison with chronic hepatitis C (CHC). CONCLUSIONS With a clinical history of approximately 11 years, occult HCV infection can be considered an occult type of CHC. Evidences suggest that considering OCI in these high-risk groups seems to be necessary. We suggest that alternative diagnostic tests should be applied and that there is a need for the participation of all countries to determine the epidemiology of this type of HCV infection. Additionally, evaluating OCI in blood transfusion centers and in patients who receive large amounts of blood and clotting factors, such as patients with hemophilia, should be performed in future projects.
Collapse
Affiliation(s)
- Mohammad Saeid Rezaee-Zavareh
- Students’ Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Middle East Liver Diseases Center (MELD), Tehran, IR Iran
| | - Reza Hadi
- Middle East Liver Diseases Center (MELD), Tehran, IR Iran
| | - Hamidreza Karimi-Sari
- Students’ Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | | | - Reza Ajudani
- Students’ Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Fardin Dolatimehr
- Students’ Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Mahdi Ramezani-Binabaj
- Students’ Research Committee, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyyed Mohammad Miri
- Middle East Liver Diseases Center (MELD), Tehran, IR Iran
- Kowsar Medical Institute, Heerlen, The Netherlands
| | - Seyed Moayed Alavian
- Middle East Liver Diseases Center (MELD), Tehran, IR Iran
- Baqiyatallah Research Center for Gasteroenterology and Liver Disease (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| |
Collapse
|
|
23
|
Kaźmierczak J, Caraballo Cortes K, Bukowska-Ośko I, Radkowski M. Virus-Specific Cellular Response in Hepatitis C Virus Infection. Arch Immunol Ther Exp (Warsz) 2015; 64:101-10. [PMID: 26429740 DOI: 10.1007/s00005-015-0364-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 06/08/2015] [Indexed: 12/15/2022]
Abstract
Studies performed on chimpanzees and humans have revealed that strong, multispecific and sustained CD4(+) and CD8(+) T cell immune responses is a major determinant of hepatitis C virus (HCV) clearance. However, spontaneous elimination of the virus occurs in minority of infected individuals and cellular response directed against HCV antigens is not persistent in individuals with chronic infection. This review presents characteristics of the HCV-specific T cell response in patients with different clinical course of infection, including acute and chronic infection, persons who spontaneously eliminated HCV and non-infected subjects exposed to HCV. Detection of HCV-specific response, especially in non-infected subjects exposed to HCV, may be indicative of HCV prevalence in population and rate of spontaneous viral clearance. Understanding the mechanisms and role of HCV-specific cellular immune response would contribute to better understanding of HCV epidemiology, immunopathogenesis and may help to design an effective vaccine.
Collapse
Affiliation(s)
- Justyna Kaźmierczak
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland.
| | - Kamila Caraballo Cortes
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| | - Iwona Bukowska-Ośko
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| |
Collapse
|
|
24
|
Abdelwahab SF, Zakaria Z, Sobhy M, Hamdy S, Mahmoud MA, Mikhail N, Allam WR, Rewisha E, Waked I. Differential distribution of IL28B.rs12979860 single-nucleotide polymorphism among Egyptian healthcare workers with and without a hepatitis C virus-specific cellular immune response. Arch Virol 2015; 160:1741-1750. [PMID: 25971683 DOI: 10.1007/s00705-015-2446-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2015] [Accepted: 04/30/2015] [Indexed: 02/08/2023]
Abstract
The CC genotype of the interleukin (IL)-28B.rs12979860 gene has been associated with spontaneous hepatitis C virus (HCV) clearance and treatment response. The distribution and correlation of an IL28B.rs12979860 single-nucleotide polymorphism (SNP) with HCV-specific cell-mediated immune (CMI) responses among Egyptian healthcare workers (HCWs) is not known. We determined this relationship in 402 HCWs who serve a patient cohort with ~85% HCV prevalence. We enrolled 402 HCWs in four groups: group 1 (n = 258), seronegative aviremic subjects; group 2 (n = 25), seronegative viremic subjects; group 3 (n = 41), subjects with spontaneously resolved HCV infection; and group 4 (n = 78), chronic HCV patients. All subjects were tested for an HCV-specific CMI response using an ex-vivo interferon-gamma (IFNγ) ELISpot assay with nine HCV genotype-4a overlapping 15-mer peptide pools corresponding to all of the HCV proteins. All subjects were tested for IL28B.rs12979860 SNP by real-time PCR. An HCV-specific CMI was demonstrated in ~27% of the seronegative aviremic HCWs (group 1), suggesting clearance of infection after low-level exposure to HCV. The frequency of IL28B.rs12979860 C allele homozygosity in the four groups was 49%, 48%, 49%, and 23%, while that of the T allele was 14%, 16%, 12 and 19%, respectively, suggesting differential distributions among subjects with different HCV status. As reported, IL28B.rs12979860 predicted the outcome of HCV infection (p < 0.05), but we did not find any relationship between the IL28B genotypes and the outcome of HCV-specific CMI responses in the four groups (p > 0.05). The data show differential IL28B.rs12979860 genotype distribution among Egyptian HCWs with different HCV status and could not predict the outcome of HCV-specific CMI responses.
Collapse
Affiliation(s)
- Sayed F Abdelwahab
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, 61511, Egypt,
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Resistance to hepatitis C virus: potential genetic and immunological determinants. THE LANCET. INFECTIOUS DISEASES 2015; 15:451-60. [PMID: 25703062 DOI: 10.1016/s1473-3099(14)70965-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Studies of individuals who were highly exposed but seronegative (HESN) for HIV infection led to the discovery that homozygosity for the Δ32 deletion mutation in the CCR5 gene prevents viral entry into target cells, and is associated with resistance to infection. Additionally, evidence for protective immunity has been noted in some HESN groups, such as sex workers in The Gambia. Population studies of individuals at high risk for hepatitis C virus infection suggest that an HESN phenotype exists. The body of evidence, which suggests that protective immunity allows clearance of hepatitis C virus without seroconversion is growing. Furthermore, proof-of-principle evidence from in-vitro studies shows that genetic polymorphisms can confer resistance to establishment of infection. This Review discusses the possibility that genetic mutations confer resistance against hepatitis C virus, and also explores evidence for protective immunity, including via genetically programmed variations in host responses. The data generally strengthens the notion that investigations of naturally arising polymorphisms within the hepatitis C virus interactome, and genetic association studies of well characterised HESN individuals, could identify potential targets for vaccine design and inform novel therapies.
Collapse
|
|
26
|
Cashman SB, Marsden BD, Dustin LB. The Humoral Immune Response to HCV: Understanding is Key to Vaccine Development. Front Immunol 2014; 5:550. [PMID: 25426115 PMCID: PMC4226226 DOI: 10.3389/fimmu.2014.00550] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 10/16/2014] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) remains a global problem, despite advances in treatment. The low cost and high benefit of vaccines have made them the backbone of modern public health strategies, and the fight against HCV will not be won without an effective vaccine. Achievement of this goal will benefit from a robust understanding of virus-host interactions and protective immunity in HCV infection. In this review, we summarize recent findings on HCV-specific antibody responses associated with chronic and spontaneously resolving human infection. In addition, we discuss specific epitopes within HCV's envelope glycoproteins that are targeted by neutralizing antibodies. Understanding what prompts or prevents a successful immune response leading to viral clearance or persistence is essential to designing a successful vaccine.
Collapse
Affiliation(s)
- Siobhán B Cashman
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford , Oxford , UK
| | - Brian D Marsden
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford , Oxford , UK ; Nuffield Department of Medicine, Structural Genomics Consortium, University of Oxford , Oxford , UK
| | - Lynn B Dustin
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford , Oxford , UK
| |
Collapse
|
|
27
|
Sugden PB, Cameron B, Mina M, Lloyd AR. Protection against hepatitis C infection via NK cells in highly-exposed uninfected injecting drug users. J Hepatol 2014; 61:738-45. [PMID: 24845613 DOI: 10.1016/j.jhep.2014.05.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 04/17/2014] [Accepted: 05/06/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS HCV seroprevalence surveys in longstanding injecting drug users (IDUs) reveal a small minority who remain seronegative, with some exhibiting HCV-specific cellular immunity. This study aimed to characterise this immunity, assess associations with risk behaviours and protection against infection. METHODS A nested case-control series from a prospective cohort of seronegative IDUs was selected with incident cases (IN; n = 28) matched by demographics and risk behaviour to exposed uninfected (EU) subjects (n = 28). Samples were assayed for natural killer (NK) cell phenotypes and function, HCV-specific IFNγ in ELISpot, and HCV-specific CD4 T effector responses. IL28B and HLA-C/KIR2DL3 genotypes were tested. RESULTS Numbers of activated (CD69(+)) NK cells in the mature CD56(dim)CD16(+) subset, and cytotoxic (NKp30(+)) cells in the CD56(bright)CD16(+) subset were higher in the EU subjects (p = 0.040, p = 0.038 respectively). EU subjects had higher frequencies of interferon gamma (IFNγ) producing NK cells, and lower frequencies of CD107a expression (p = 0.003, p = 0.015 respectively). By contrast, the frequency, magnitude, and breadth of HCV-specific CD4 and CD8 T cell responses did not differ, nor did IL28B, HLA-C, or KIR2DL3 allele frequencies. CONCLUSIONS Sustained NK cell activation contributes to protection against HCV infection. HCV-specific cellular immunity is prevalent in EU subjects but does not appear to be protective.
Collapse
MESH Headings
- Adult
- Antigens, CD/immunology
- Antigens, Differentiation, T-Lymphocyte/immunology
- Drug Users/psychology
- Female
- Gene Expression Profiling
- Hepatitis C/etiology
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/prevention & control
- Humans
- Interferons
- Interleukins/genetics
- Interleukins/immunology
- Killer Cells, Natural/immunology
- Lectins, C-Type/immunology
- Lymphocyte Activation/immunology
- Male
- Natural Cytotoxicity Triggering Receptor 3/immunology
- Receptors, KIR2DL3/genetics
- Receptors, KIR2DL3/immunology
- Risk-Taking
- Substance Abuse, Intravenous/complications
- Substance Abuse, Intravenous/genetics
- Substance Abuse, Intravenous/immunology
- Substance Abuse, Intravenous/psychology
Collapse
Affiliation(s)
- Peter B Sugden
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Barbara Cameron
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia.
| | - Michael Mina
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Andrew R Lloyd
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, Australia
| |
Collapse
|
|
28
|
Musyoki AM, Msibi TL, Motswaledi MH, Selabe SG, Monokoane TS, Mphahlele MJ. Active co-infection with HBV and/or HCV in South African HIV positive patients due for cancer therapy. J Med Virol 2014; 87:213-21. [PMID: 25156907 DOI: 10.1002/jmv.24055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2014] [Indexed: 01/20/2023]
Abstract
Human immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV) share routes of transmission. There is limited data on the incidence of active co-infection with HBV and/or HCV in cancer patients infected with HIV in Africa. This was a prospective study based on 34 patients with varied cancer diagnosis, infected with HIV and awaiting cancer therapy in South Africa. HIV viral load, CD4+ cell counts, Alanine-aminotransferase and aspartate aminotransferase levels were tested. Exposure to HBV and HCV was assessed serologically using commercial kits. Active HBV and/or HCV co-infection was detected using viral specific nested PCR assays. HCV 5'-UTR PCR products were sequenced to confirm active HCV infection. Active viral infection was detected in 64.7% of patients for HBV, 38.2% for HCV, and 29.4% for both HBV and HCV. Occult HBV infection was observed in 63.6% of the patients, while seronegative HCV infection was found in 30.8% of patients. In addition, CD4+ cell count < 350 cells/µl was not a risk factor for increased active HBV, HCV or both HBV and HCV co-infections. A total of 72.7%, 18.2% and 9.1% of the HCV sequences were assigned genotype 5, 1 and 4 respectively.The study revealed for the first time a high active HBV and/or HCV co-infection rate in cancer patients infected with HIV. The findings call for HBV and HCV testing in such patients, and where feasible, appropriate antiviral treatment be indicated, as chemotherapy or radiotherapy has been associated with reactivation of viral hepatitis and termination of cancer therapy.
Collapse
Affiliation(s)
- Andrew M Musyoki
- HIV and Hepatitis Research Unit, Department of Virology, University of Limpopo (Medunsa Campus) and National Health Laboratory Service, Pretoria, South Africa
| | | | | | | | | | | |
Collapse
|
|
29
|
Hetta HF, Mehta MJ, Shata MTM. Gut immune response in the presence of hepatitis C virus infection. World J Immunol 2014; 4:52-62. [DOI: 10.5411/wji.v4.i2.52] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 05/22/2014] [Accepted: 06/20/2014] [Indexed: 02/05/2023] Open
Abstract
Hepatitis C virus (HCV) is an important etiologic agent of hepatitis and a major cause of chronic liver infection that often leads to cirrhosis, fibrosis and hepatocellular carcinoma. Although, HCV is a hepatotropic virus, there is strong evidence that HCV could replicate extra-hepatic in the gastrointestinal tissue which could serve as a reservoir for HCV. The outcome of HCV infection depends mainly on the host innate and adaptive immune responses. Innate immunity against HCV includes mainly nuclear factor cells and activation of IFN-related genes. There is an immunologic link between the gut and the liver through a population of T-cells that are capable of homing to both the liver and gut via the portal circulation. However, little is known on the role of Gut immune response in HCV. In this review we discussed the immune regulation of Gut immune cells and its association with HCV pathogenesis, various outcomes of anti-HCV therapy, viral persistence and degree of liver inflammation. Additionally, we investigated the relationship between Gut immune responses to HCV and IL28B genotypes, which were identified as a strong predictor for HCV pathogenesis and treatment outcome after acute infection.
Collapse
|
|
30
|
Kisiel E, Radkowski M, Pawelczyk A, Horban A, Stanczak J, Bukowska-Ośko I, Caraballo Cortes K, Kaźmierczak J, Popiel M, Laskus T. Seronegative hepatitis C virus infection in patients with lymphoproliferative disorders. J Viral Hepat 2014; 21:424-9. [PMID: 24138606 DOI: 10.1111/jvh.12181] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
It has been reported that hepatitis C virus (HCV) RNA may be present in serum and/or lymphoid cells in the absence of specific circulating antibodies. The current study analysed seronegative HCV infection in patients with lymphoproliferative disorders. We studied 77 anti-HCV-negative patients (45 male and 32 female, mean age 54.8 ± 14.2 years) with various lymphoproliferative disorders. HCV-RNA was detected by RT-PCR in plasma, peripheral blood mononuclear cells (PBMC) and bone marrow. Furthermore, the presence of viral nonstructural protein 3 (NS3) was determined in PBMC and bone marrow by immunostaining. HCV-RNA was detectable in at least one compartment in 27 (35.1%) patients. Viral RNA was found in bone marrow in 22 patients (28.6%), in PBMC in 13 (16.9%) and in plasma in 10 (13%) patients. In nine patients, evidence of infection was confined to the bone marrow compartment. Viral load in HCV-RNA-positive plasma ranged from 15 to 1.17 × 10(3) IU/mL. NS3 was detected in all but two HCV-RNA-positive bone marrow samples and in all but one HCV-RNA-positive PBMC samples. All 27 HCV-RNA-positive patients remained anti-HCV-negative when tested again after 6-12 months, but only four remained HCV-RNA positive. In conclusion, among patients with lymphoproliferative disorders, HCV can be present in plasma, PBMC and bone marrow despite the lack of circulating specific antibodies. Further studies are required to analyse the phenomenon of seronegative infection and to determine whether such patients are infectious.
Collapse
Affiliation(s)
- E Kisiel
- Department of Hematology, Institute of Hematology and Blood Transfusion, Warsaw, Poland
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Reiche S, Nestler C, Sieg M, Schulz K, Cordes C, Krznaric I, Jassoy C. Hepatitis C virus (HCV)-specific memory B-cell responses in transiently and chronically infected HIV positive individuals. J Clin Virol 2014; 59:218-22. [PMID: 24566009 DOI: 10.1016/j.jcv.2014.01.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 12/03/2013] [Accepted: 01/17/2014] [Indexed: 01/27/2023]
Abstract
BACKGROUND Antibody responses to hepatitis C virus (HCV) occur delayed and overly decline after viral clearance indicating that the B-cell response to HCV is abnormal. Virus-specific memory B-cells have recently been found in infected individuals, but the viral exposure requirements for the generation of these cells is unknown. OBJECTIVES The primary goal of this study was to quantify and compare the HCV-specific memory B-cell response between chronic and resolved HCV-infected individuals. A secondary goal was to examine if HIV-specific memory B-cell responses are maintained during HCV co-infection. STUDY DESIGN HCV core protein- and HIV-specific memory B-cell responses were examined in HIV/HCV-infected individuals treated 4-30 weeks after HCV diagnosis. Memory B-cell frequencies were compared between chronically and transiently infected individuals. RESULTS Chronically infected individuals had vigorous HCV-specific memory B-cell responses and antibodies, whereas subjects with transient viremia showed low or undetectable virus-specific B-cell responses. In addition, chronically HIV/HCV-infected subjects had robust HIV-specific memory B-cell responses. CONCLUSIONS Whereas chronic HCV infection induces virus-specific antibodies and memory B-cells, transient infection in individuals with sustained viral response to therapy does not stimulate a durable HCV-specific B-cell response indicating that the formation of long-lived virus-specific B-cells is suppressed in the early phase of infection. This may contribute to the inability to spontaneously clear HCV infection.
Collapse
Affiliation(s)
- Sven Reiche
- Institute of Virology, Faculty of Medicine, University of Leipzig, 04105 Leipzig, Germany
| | - Claudia Nestler
- Institute of Virology, Faculty of Medicine, University of Leipzig, 04105 Leipzig, Germany
| | - Michael Sieg
- Institute of Virology, Faculty of Medicine, University of Leipzig, 04105 Leipzig, Germany
| | - Katharina Schulz
- Institute of Virology, Faculty of Medicine, University of Leipzig, 04105 Leipzig, Germany
| | | | | | - Christian Jassoy
- Institute of Virology, Faculty of Medicine, University of Leipzig, 04105 Leipzig, Germany.
| |
Collapse
|
|
32
|
Kamal SM, Kassim SK, Ahmed AI, Mahmoud S, Bahnasy KA, Hafez TA, Aziz IA, Fathelbab IF, Mansour HM. Host and viral determinants of the outcome of exposure to HCV infection genotype 4: a large longitudinal study. Am J Gastroenterol 2014; 109:199-211. [PMID: 24445571 DOI: 10.1038/ajg.2013.427] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 10/16/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The objective of this study was to characterize the factors that influence the outcome of exposure to hepatitis C virus (HCV) genotype 4 (HCV-G4) and the course of recent infection. METHODS In this longitudinal study, we prospectively assessed the clinical, genetic, virological, and immunological parameters and retrospectively determined single-nucleotide polymorphisms at interleukin-28B (IL-28B) rs12979860 in a well-characterized large cohort recently exposed to HCV-G4. RESULTS A total of 136 subjects with acute HCV (new viremia, seroconversion, and HCV-specific T-cell responses) were identified. Forty-eight subjects (35%) had spontaneous viral clearance and 88 subjects developed chronic HCV of which 42 subjects were treated with pegylated interferon monotherapy, with a sustained virologic response (SVR) rate of 88%. Twenty-six subjects developed HCV-specific T-cell immune responses without detectable viremia or seroconversion. IL-28B-CC (odds ratio (OR) 14.22; P<0.0001), multispecific T-cell responses (OR=11.66; P<0.0001), >300 IU/l alanine aminotransferase (ALT) decline within 4 weeks (OR=6.83; P<0.0001), jaundice (OR=3.54; P=0.001), female gender (OR=2.39; P=0.007), and >2.5 log10 HCV-RNA drop within 8 weeks (OR=2.48; P=0.016) were independently associated with spontaneous clearance. ALT normalization and undetectable HCV-RNA predicted SVR. Exposed apparently uninfected participants had a higher frequency of IL-28B-CC than patients with unresolved acute HCV (P<0.001). IL-28B-CC was associated with multispecific T-cell response (r(2)=0.0.835; P<0.001). CONCLUSIONS IL-28B-CC genotype, multispecific HCV T-cell responses, rapid decline in ALT, and viral load predict spontaneous clearance and response to acute HCV-G 4 therapy. IL-28B-CC genotype correlates with developing early multispecific T-cell responses. These findings have important implications for predicting the outcome of HCV exposure and acute infection and identifying patients likely to benefit from therapy.
Collapse
Affiliation(s)
- Sanaa M Kamal
- Department of Infectious Diseases, Gastroenterology and Tropical Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt
| | - Samar K Kassim
- Department of Molecular Biology and Biochemistry, Ain Shams Faculty of Medicine, Cairo, Egypt
| | - Amany I Ahmed
- Department of Infectious Diseases, Gastroenterology and Tropical Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt
| | - Sara Mahmoud
- Department of Infectious Diseases, Gastroenterology and Tropical Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt
| | - Khaled A Bahnasy
- Department of Biostatistics and Bioinformatics, Ain Shams University, Cairo, Egypt
| | - Tamer A Hafez
- Department of Molecular Biology and Genetics, The American University in Cairo, Egypt
| | - Ibrahiem A Aziz
- Department of Tropical Medicine, Al Azhar Faculty of Medicine, Cairo, Egypt
| | | | | |
Collapse
|
|
33
|
Matovina-Brko G, Ruzic M, Fabri M, Popovic L, Kolarov-Bjelobrk I, Trifunovic J, Petkovic D. Treatment of acute hepatitis C in breast cancer patient: a case report. J Chemother 2013; 26:180-3. [DOI: 10.1179/1973947813y.0000000129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
|
|
34
|
Spengler U, Nischalke HD, Nattermann J, Strassburg CP. Between Scylla and Charybdis: The role of the human immune system in the pathogenesis of hepatitis C. World J Gastroenterol 2013; 19:7852-7866. [PMID: 24307779 PMCID: PMC3848133 DOI: 10.3748/wjg.v19.i44.7852] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 10/25/2013] [Accepted: 11/13/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) frequently elicits only mild immune responses so that it can often establish chronic infection. In this case HCV antigens persist and continue to stimulate the immune system. Antigen persistence then leads to profound changes in the infected host’s immune responsiveness, and eventually contributes to the pathology of chronic hepatitis. This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity (interferons, natural killer cells), adaptive immune responses (immunoglobulins, T cells, and mechanisms of immune regulation (regulatory T cells). Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage. In chronic hepatitis C, however, the effector arms of the immune system either become refractory to activation or take over regulatory functions. Taken together these changes in immunity may lead to persistent liver damage and cirrhosis. Consequently, effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation, necrosis and progression to cirrhosis. Thus, avoiding Scylla - a strong, sustained antiviral immune response with inital tissue damage - takes the infected host to virus-triggered immunopathology, which ultimately leads to cirrhosis and liver cancer - the realm of Charybdis.
Collapse
|
|
35
|
Progress towards a hepatitis C virus vaccine. Emerg Microbes Infect 2013; 2:e79. [PMID: 26038445 PMCID: PMC3924556 DOI: 10.1038/emi.2013.79] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2013] [Revised: 10/01/2013] [Accepted: 10/09/2013] [Indexed: 12/16/2022]
Abstract
New drugs to treat hepatitis C are expected to be approved over the next few years which promise to cure nearly all patients. However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world's HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections. For these reasons, there is an urgent need to develop a prophylactic HCV vaccine and also to determine if therapeutic vaccines can aid in the treatment of chronically infected patients. After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism. This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus.
Collapse
|
|
36
|
Kaźmierczak J, Pawełczyk A, Cortes KC, Radkowski M. Seronegative hepatitis C virus infection. Arch Immunol Ther Exp (Warsz) 2013; 62:145-51. [PMID: 24202543 PMCID: PMC3950562 DOI: 10.1007/s00005-013-0257-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 10/25/2013] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease worldwide. The routine diagnostics identifying HCV infection include testing for specific anti-HCV antibodies by enzyme-linked immnunosorbent assay and viral genetic material in serum or plasma. However, a small proportion of patients persistently infected with HCV, in whom anti-HCV are undetectable, constitute a serious diagnostic and possibly epidemiologic problem, as they could facilitate pathogen spread in the population. This type of infection is termed seronegative or serosilent. Seronegative HCV infection is currently of great interest to both scientists and physicians. The review presents epidemiological data concerning the prevalence of seronegative HCV infection in HIV/HCV co-infected individuals, hemodialysis patients, and blood and organ donors. The possible mechanisms behind this atypical course of infection are discussed. Furthermore, the differences between seronegative and occult infections and prolonged seroconversion are explained.
Collapse
Affiliation(s)
- Justyna Kaźmierczak
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Warsaw, Poland,
| | | | | | | |
Collapse
|
|
37
|
Sugden PB, Pham TNQ, Ratnarajah S, Cameron B, Bull R, White PA, Michalak TI, Lloyd AR. Rare occurrence of occult hepatitis C virus in apparently uninfected injecting drug users: a two-centre, masked, case-control study. J Viral Hepat 2013; 20:725-8. [PMID: 24010647 DOI: 10.1111/jvh.12098] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2012] [Accepted: 02/05/2013] [Indexed: 02/03/2023]
Abstract
Occult hepatitis C virus (HCV) is a phenomenon where serum HCV RNA is not detected by sensitive commercial assays, but viral RNA is detected by ultrasensitive techniques. Occult HCV infection has not previously been studied in highly exposed, but apparently uninfected (EU) individuals. Two studies examining occult infection in EU subjects were undertaken - an initial two-centre, masked, case-control study based on cross-sectional samples (n = 35 subjects) and a single-centre confirmatory study based on longitudinal samples (n = 32 subjects). Plasma and peripheral blood mononuclear cells were tested for HCV RNA using an ultrasensitive nested polymerase chain reaction assays. Two EU subjects in the first study (10%) and one in the second study (3%) were found to have consistently detectable HCV RNA. Occult HCV infection occurs in high-risk, apparently uninfected subjects.
Collapse
Affiliation(s)
- P B Sugden
- Inflammation and Infection Research Centre, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Liang TJ. Current progress in development of hepatitis C virus vaccines. Nat Med 2013; 19:869-78. [PMID: 23836237 PMCID: PMC6263146 DOI: 10.1038/nm.3183] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 02/22/2013] [Indexed: 12/14/2022]
Abstract
Despite major advances in the understanding and treatment of hepatitis C, a preventive vaccine remains elusive. The marked genetic diversity and multiple mechanisms of persistence of hepatitis C virus, combined with the relatively poor immune response of the infected host against the virus, are major barriers. The lack of robust and convenient model systems further hampers the effort to develop an effective vaccine. Advances in our understanding of virus-host interactions and protective immunity in hepatitis C virus infection provide an important roadmap to develop potent and broadly directed vaccine candidates targeting both humoral and cellular immune responses. Multiple approaches to generating and testing viral immunogens have met with variable success. Several candidates have advanced to clinical trials based on promising results in chimpanzees. The ultimate path to a successful preventive vaccine requires comprehensive evaluations of all aspects of protective immunity, innovative application of state-of-the-art vaccine technology and properly designed vaccine trials that can affirm definitive endpoints of efficacy.
Collapse
Affiliation(s)
- T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
| |
Collapse
|
|
39
|
Rafik MM, Hosny AEDMS, Abdallah KO, Abbas AA, Abo Shady RA, Soliman DA, Nasr El-Din Rakha KM, Alfedawy SF. TH1 cytokine response to HCV peptides in Egyptian health care workers: a pilot study. Virol J 2013; 10:144. [PMID: 23663415 PMCID: PMC3655851 DOI: 10.1186/1743-422x-10-144] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2012] [Accepted: 05/03/2013] [Indexed: 12/24/2022] Open
Abstract
Our objective was to elucidate the effects of different HCV peptides on TH1 cytokine synthesis (interleukin 2(IL2), gamma interferon (INFγ) and tumor necrosis factor α (TNF α)), in a proliferative response in a high risk population of HCV seronegative aviremic Egyptian healthcare workers (HCW). We studied the TH1 cytokine response to different HCV peptides among 47 HCW with and without evidence of HCV infection. Participants were classified according to the proliferation index (PI) in a CFSE proliferation assay as an indicator of previous exposure to HCV. Cytokines were analyzed using Luminex xMAP technology. Results showed that positive PI HCW produced a higher IL2 in response to all HCV peptides except NS4, a higher IFNγ response to NS3 and NS4 and no difference in TNFα response when compared to the negative PI HCWs. When compared to chronic HCV HCW, positive PI HCW showed no difference in the IL2 response, a higher IFNγ response to NS4 and NS5 HCV peptides and a higher TNFα response to all peptides. In conclusion the magnitude and type of cytokines produced in HCV infection is critical in determining the outcome of infection. NS4 & NS5 HCV peptides induce a protective TH1 response in positive PI HCW.
Collapse
Affiliation(s)
- Mona M Rafik
- Ain Shams Faculty of Medicine Clinical Pathology Department, Abbassia square, Cairo, Egypt.
| | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Abstract
Introduction With 3 – 4 million new infections occurring annually, hepatitis C virus (HCV) is a major global health problem. There is increasing evidence to suggest that HCV will be highly amenable to a vaccine approach, and despite advances in treatment, a vaccine remains the most cost-effective and realistic means to significantly reduce the worldwide mortality and morbidity associated with persistent HCV infection. Areas covered In this review we discuss immune responses to HCV during natural infection, and describe how they may inform vaccine design. We introduce the current candidate vaccines for HCV and compare how these fare against the expected requirements of an effective prophylactic HCV vaccine in relation to the breadth, functionality, magnitude and phenotype of the vaccine-induced immune response. Expert opinion Although the correlates of immune protection against HCV are not completely defined, we now have vaccine technologies capable of inducing HCV-specific adaptive immune responses to an order of magnitude that are associated with protection during natural infection. The challenge next is to i) establish well-characterised cohorts of people at risk of HCV infection for vaccine efficacy testing and ii) to better understand the correlates of protection in natural history studies. If these can be achieved, a vaccine against HCV appears a realistic goal.
Collapse
Affiliation(s)
- Leo Swadling
- University of Oxford, NDM and Jenner Institute, Peter Medawar Building, South Parks Road, Oxford, OX1 3SY, UK
| | | | | |
Collapse
|
|
41
|
Abdelwahab SF, Hashem M, Galal I, Sobhy M, Abdel-Ghaffar TS, Galal G, Mikhail N, El-Kamary SS, Waked I, Strickland GT. Incidence of hepatitis C virus infection among Egyptian healthcare workers at high risk of infection. J Clin Virol 2013; 57:24-28. [PMID: 23375237 DOI: 10.1016/j.jcv.2013.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2012] [Revised: 12/28/2012] [Accepted: 01/03/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a global health threat with Egypt having the highest worldwide prevalence. Evaluation of the efficacy of a preventive HCV vaccine, such as those currently in Phase I/II trials, requires a cohort with a high-risk exposure to HCV. OBJECTIVE To identify a reliable cohort for evaluating preventive HCV vaccines, we studied HCV incidence among HCW in a hospital where almost 85% of patients are HCV-infected. STUDY DESIGN Of 717 HCW negative for HCV-antibodies (anti-HCV) at baseline, 651 were followed up and tested for seroconversion twice annually for an average of 504 ± 154 days. Those reporting a needle-stick injury were additionally tested for both HCV antibodies and RNA monthly for a total of four months. RESULTS Two subjects (0.31%) had anti-HCV and HCV-RNA seroconversion with an overall incidence of 2.04/1000 person-years and a 4.8% incidence among the 21 subjects who reported a needle-stick injury. Two additional subjects had viremia without detectable anti-HCV. Two of the four subjects were among 21 with reported needle-stick injuries (9.5%) and another had surgery. All four were nurses providing direct patient care. CONCLUSIONS Our results show that both transient and persistent viremia were detectable in this high-risk cohort of HCW and suggest that absence of anti-HCV in two of the subjects may be due to low-dose viral exposures. These data indicate that HCV infections acquired from documented injuries during direct patient care are frequent in Egypt and can guide selection of eligible HCW suitable for preventive HCV vaccine trials.
Collapse
Affiliation(s)
- Sayed F Abdelwahab
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Choi YS, Lee JE, Nam SJ, Park JT, Kim HS, Choi KH, Kim BS, Shin EC. Two distinct functional patterns of hepatitis C Virus (HCV)-specific T cell responses in seronegative, aviremic patients. PLoS One 2013; 8:e62319. [PMID: 23638039 PMCID: PMC3640053 DOI: 10.1371/journal.pone.0062319] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 03/20/2013] [Indexed: 12/13/2022] Open
Abstract
In hepatitis C Virus (HCV) high-risk groups, HCV-specific T cell responses have been detected in seronegative, aviremic persons who have no evidence of HCV infection. Herein, we investigated functional profiles of HCV-specific T-cell responses in seronegative, aviremic patients of a HCV high-risk group. Seventy seven hemodialysis patients with chronic renal disease were analyzed by IFN-γ ELISpot assays, and eight of 71 (11.3%) seronegative, aviremic patients displayed HCV-specific T-cell responses. Their HCV-specific memory T cells were characterized by assessing cytokine polyfunctionality, known to provide antiviral protection. By intracellular staining of IFN-γ, TNF-α, IL-2 and MIP-1β, we identified two distinct populations in the seronegative, aviremic patients: polyfunctional responders and TNF-α-predominant responders. In further analysis, occult HCV infection was excluded as a cause of the HCV-specific T cell response via secondary nested RT-PCR of HCV RNA in peripheral blood mononuclear cell samples. HCV-specific T cells targeted multiple epitopes including non-structural proteins in a single patient, implying that their T cells might have been primed by HCV proteins synthesized within the host. We conclude that HCV-specific memory T cells of seronegative, aviremic patients arise from authentic HCV replication in the host, but not from current occult HCV infection. By functional pattern of HCV-specific T cells, there are two distinct populations in these patients: polyfunctional responders and TNF-α-predominant responders.
Collapse
Affiliation(s)
- Yoon Seok Choi
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Jung Eun Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Joo Nam
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
| | - Jung Tak Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyon-Suk Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Kyu Hun Choi
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Beom Seok Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- * E-mail: (ES); (BK)
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea
- * E-mail: (ES); (BK)
| |
Collapse
|
|
43
|
Cameron B, Galbraith S, Li H, Lloyd A. Correlates and characteristics of hepatitis C virus-specific T-cell immunity in exposed uninfected high-risk prison inmates. J Viral Hepat 2013; 20:e96-106. [PMID: 23490396 DOI: 10.1111/jvh.12016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 08/01/2012] [Indexed: 01/04/2023]
Abstract
Some hepatitis C (HCV)-uninfected, high-risk individuals have HCV-specific cellular immunity without viraemia or seroconversion. The characteristics of these responses and the risk behavioural associations were studied in 94 subjects in a prospective cohort of recently seronegative prisoners reporting injecting drug use (IDU). Detailed behavioural data were collected. HCV antibody and PCR testing were performed. ELISpot assays for HCV-induced interferon (IFN)-γ and interleukin (IL)-2 production by T lymphocytes, as well as multiplex in vitro cytokine production assays, were performed. Seventy-eight subjects remained antibody and PCR negative and 16 seroconverted. Of the seronegative group, 22 (28%) had IFN-γ ELISpot responses in comparison with 13 of the 16 seroconverters (82%). This seronegative immune status was associated positively with injecting anabolic steroids and negatively with a recent break from IDU. The IFN-γ ELISpot responses involved both CD4 and CD8 T lymphocytes and were comparable in magnitude, but narrower in specificity, in uninfected subjects than in seroconverters. A subset of seronegative subjects had HCV-induced cytokine production patterns comparable with the seroconverters with increased production of IFN-γ, IL-2 and tumour necrosis factor (TNF)-α and reduced IL-10 in response to nonstructural peptides. In conclusion, comparable patterns of HCV-specific cellular immunity are found in recently infected subjects and in a minority of high-risk, uninfected subjects. Further characterization of these responses and their protective efficacy will inform HCV vaccine development.
Collapse
Affiliation(s)
- B Cameron
- Inflammation and Infection Research Centre, School of Medical Sciences, Sydney, NSW, Australia.
| | | | | | | | | |
Collapse
|
|
44
|
Munier A, Marzouk D, Abravanel F, El-Daly M, Taylor S, Mamdouh R, Eldin WS, El-Arab HE, Sos DG, Momen M, Okasha O, Le Fouler L, El-Hosini M, Izopet J, Rafik M, Albert M, Abdel-Hamid M, Mohamed MK, Delarocque-Astagneau E, Fontanet A. Frequent transient hepatitis C viremia without seroconversion among healthcare workers in Cairo, Egypt. PLoS One 2013; 8:e57835. [PMID: 23469082 PMCID: PMC3585182 DOI: 10.1371/journal.pone.0057835] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 01/26/2013] [Indexed: 02/06/2023] Open
Abstract
Backgrounds With 10% of the general population aged 15–59 years chronically infected with hepatitis C virus (HCV), Egypt is the country with the highest HCV prevalence worldwide. Healthcare workers (HCWs) are therefore at particularly high risk of HCV infection. Our aim was to study HCV infection risk after occupational blood exposure among HCWs in Cairo. Methodology/Principal Findings The study was conducted in 2008–2010 at Ain Shams University Hospital, Cairo. HCWs reporting an occupational blood exposure at screening, having neither anti-HCV antibodies (anti-HCV) nor HCV RNA, and exposed to a HCV RNA positive patient, were enrolled in a 6-month prospective cohort with follow-up visits at weeks 2, 4, 8, 12 and 24. During follow-up, anti-HCV, HCV RNA and ALT were tested. Among 597 HCWs who reported a blood exposure, anti-HCV prevalence at screening was 7.2%, not different from that of the general population of Cairo after age-standardization (11.6% and 10.4% respectively, p = 0.62). The proportion of HCV viremia among index patients was 37%. Of 73 HCWs exposed to HCV RNA from index patients, nine (12.3%; 95%CI, 5.8–22.1%) presented transient viremia, the majority of which occurred within the first two weeks after exposure. None of the workers presented seroconversion or elevation of ALT. Conclusions/Significance HCWs of a general University hospital in Cairo were exposed to a highly viremic patient population. They experienced frequent occupational blood exposures, particularly in early stages of training. These exposures resulted in transient viremic episodes without established infection. These findings call for further investigation of potential immune protection against HCV persistence in this high risk group.
Collapse
Affiliation(s)
- Aline Munier
- Emerging Diseases Epidemiology Unit, Institut Pasteur, Paris, France.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Mohamed HI, Saad ZM, Abd-Elreheem EM, Abd-ElGhany WM, Mohamed MS, Abd Elnaeem EA, Seedhom AE. Hepatitis C, hepatitis B and HIV infection among Egyptian prisoners: seroprevalence, risk factors and related chronic liver diseases. J Infect Public Health 2013; 6:186-95. [PMID: 23668463 DOI: 10.1016/j.jiph.2012.12.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Revised: 12/07/2012] [Accepted: 12/15/2012] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIM Prisons in Egypt do not currently screen for blood-borne viruses, and there are no statistics concerning the prevalence of hepatitis C virus, hepatitis B virus or human immunodeficiency virus among prisoners. This study was performed to detect the prevalence of antibodies against hepatitis C, hepatitis B core and human immunodeficiency virus among Egyptian prisoners. METHODS The study was conducted in an Egyptian prison. The prisoners voluntarily completed a risk factor questionnaire and provided blood specimens for testing for antibodies against hepatitis C virus, hepatitis B virus core antigen and human immunodeficiency virus. Positive results were confirmed by the detecting HCV RNA via polymerase chain reaction. Multivariate regression analysis was performed to determine the factors that were independently associated with positive HCV serology. RESULTS Five hundred resident prisoners were screened. The prevalence of hepatitis C virus antibodies was 15.8% (79/500), and viremia was confirmed by PCR in 77.2% (61/79) of the antibody-positive prisoners. The prevalence of antibodies to hepatitis B core antigen was 9.8% (49/500), and 1.2% (6/500) of prisoners were dually infected with HBV and HCV. Antibodies to human immunodeficiency virus were not detected in any of the prisoners. The best predictor for hepatitis C and hepatitis B infection was a history of intravenous drug use (P<0.011 for HBV and P<0.001 for HCV), a period of >10 years spent in prison (P<0.052 for HBV and P<0.021 for HCV) and shared toiletries (P<0.059 for HBV and P<0.002 for HCV). CONCLUSION Hepatitis C and hepatitis B virus infections constitute an important public health problem in prisons. Public health strategies to prevent morbidity and mortality from these infections should include hepatitis B vaccination, HCV testing, counseling and medical management of infected prisoners.
Collapse
Affiliation(s)
- Hala I Mohamed
- Department of Tropical Medicine, Minia University, Egypt.
| | | | | | | | | | | | | |
Collapse
|
|
46
|
El-Kamary SS, Hashem M, Saleh DA, Abdelwahab SF, Sobhy M, Shebl FM, Shardell MD, Strickland GT, Shata MT. Hepatitis C virus-specific cell-mediated immune responses in children born to mothers infected with hepatitis C virus. J Pediatr 2013; 162:148-154. [PMID: 22883419 PMCID: PMC3526784 DOI: 10.1016/j.jpeds.2012.06.057] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2011] [Revised: 05/11/2012] [Accepted: 06/28/2012] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To investigate the association between hepatitis C virus (HCV)-specific cell-mediated immunity (CMI) responses and viral clearance in children born to mothers infected with HCV. STUDY DESIGN A cross-sectional study of children from a mother-infant cohort in Egypt were enrolled to detect CMI responses to recombinant core and nonstructural HCV antigens (nonstructural segments NS3, NS4a/b, and NS5 of the HCV genome) using an interferon-gamma enzyme-linked immunospot assay. Children born to mothers with chronic HCV were enrolled into 3 groups: transiently viremic (n = 5), aviremic (n = 36), and positive control (n = 6), which consisted of 1 child with chronic HCV from this cohort and another 5 children with chronic HCV from a companion study. Children without HCV born to mothers without HCV (n = 27) served as a negative control group. Wilcoxon rank sum test was used to compare the magnitude of CMI responses between groups. RESULTS None of the 6 control children who were positive for HCV responded to any HCV antigen, and 4 (80%) of 5 children with transient viremia responded to at least one HCV antigen, compared with 5 (14%) of 36 and 3 (11%) of 27 children in the aviremic and negative control groups, respectively. Children with transient viremia elicited stronger responses than did negative controls (P = .005), positive controls (P = .011), or children without HCV viremia (P = .012), particularly to nonstructural antigens. CONCLUSIONS HCV-specific CMI responses were significantly higher in magnitude and frequency among transiently infected children compared with those persistently infected. This suggests CMI responses may be associated with past viral clearance and can identify children at high risk of infection, who can be targeted for health education, screening, and follow-up.
Collapse
Key Words
- anti-hcv, antibodies to hepatitis c virus
- cmi, cell-mediated immunity
- elispot, enzyme-linked immunospot assay
- hcv, hepatitis c virus
- ifn-γ, interferon-gamma
- ns3/ns4, nonstructural segments ns3, ns4a, and ns4b of the hcv genome
- ns5, nonstructural segment ns5 of the hcv genome
- pbmc, peripheral blood mononuclear cell
- sfc, spot-forming cell
Collapse
Affiliation(s)
- Samer S El-Kamary
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Alvarez-Lajonchere L, Dueñas-Carrera S. Complete definition of immunological correlates of protection and clearance of hepatitis C virus infection: a relevant pending task for vaccine development. Int Rev Immunol 2012; 31:223-42. [PMID: 22587022 DOI: 10.3109/08830185.2012.680552] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatitis C virus (HCV) infects approximately 3% of global population. This pathogen is one of the main causes of chronic viral hepatitis, cirrhosis, and liver cancer, as well as the principal reason for liver transplant in Western countries. Therapy against HCV infection is effective in only half of treated patients. There is no vaccine available against HCV. Some vaccine candidates have reached the clinical trials but several factors, including the incomplete definition of immunological correlates of protection and treatment-related clearance have slowed down vaccine development. Precisely, the present review discusses the state of the art in the establishment of parameters related with immunity against HCV. Validity and limitations of the information accumulated from chimpanzees and other animal models, analysis of studies in humans infected with HCV, and relevance of aspects like type, strength, duration, and specificity of immune response related to successful outcome are evaluated in detail. Moreover, the immune responses induced in some clinical trials with vaccine candidates resemble the theoretical immunological correlates, raising questions about the validity of those correlates. When all facts are taken together, complete definition of immunological correlates for protection or treatment-related clearance is an urgent priority. A limited or wrong criterion with respect to this relevant matter might cause incorrect vaccine design and selection of immunization strategies or erroneous clinical evaluation.
Collapse
|
|
48
|
Zignego AL, Giannini C, Gragnani L, Piluso A, Fognani E. Hepatitis C virus infection in the immunocompromised host: a complex scenario with variable clinical impact. J Transl Med 2012; 10:158. [PMID: 22863056 PMCID: PMC3441205 DOI: 10.1186/1479-5876-10-158] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2012] [Accepted: 07/11/2012] [Indexed: 02/07/2023] Open
Abstract
The relationship between Hepatitis C Virus (HCV) infection and immunosuppression is complex and multifaceted. Although HCV-related hepatocytolysis is classically interpreted as secondary to the attack by cytotoxic T lymphocytes against infected cells, the liver disease is usually exacerbated and more rapidly evolutive in immunosuppressed patients. This generally occurs during the immunosuppression state, and not at the reconstitution of the host response after immunosuppressive therapy discontinuation. The field of immunosuppression and HCV infection is complicated both by the different outcome observed in different situations and/or by contrasting data obtained in the same conditions, with several still unanswered questions, such as the opportunity to modify treatment schedules in the setting of post-transplant follow-up. The complexity of this field is further complicated by the intrinsic tendency of HCV infection in itself to lead to disorders of the immune system. This review will briefly outline the current knowledge about the pathogenesis of both hepatic and extrahepatic HCV-related disorders and the principal available data concerning HCV infection in a condition of impairment of the immune system. Attention will be especially focused on some conditions - liver or kidney transplantation, the use of biologic drugs and cancer chemotherapy - for which more abundant and interesting data exist.
Collapse
Affiliation(s)
- Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Internal Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy.
| | | | | | | | | |
Collapse
|
|
49
|
Zeremski M, Makeyeva J, Arasteh K, Des Jarlais DC, Talal AH. Hepatitis C virus-specific immune responses in noninjecting drug users. J Viral Hepat 2012; 19:554-9. [PMID: 22762139 PMCID: PMC3433847 DOI: 10.1111/j.1365-2893.2011.01573.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Noninjection drug use, although recognized as an emerging risk factor for acquisition of other blood-born pathogens, is still unconfirmed as a route of hepatitis C virus (HCV) transmission. Our goal was to measure HCV exposure and prevalence in noninjection drug users (NIDUs). Fifty-seven NIDUs were screened by extensive questionnaire to exclude prior injection drug use and evaluated for HCV-specific serologic and cellular immune responses. HCV-specific T-cell responses were measured using interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot) assay with overlapping HCV peptides covering the entire HCV genome. Fifteen individuals who never used illicit drugs served as negative controls. Eleven people with no history of injecting drug use (19.3%) were HCV seropositive: seven with chronic HCV infection and four with previously resolved infection. Of 51 NIDUs with ELISpot results, HCV-specific cellular immunity was detected in 5 (9.8%). These responses were relatively weak and narrow. We did not find significant associations between HCV-specific immune responses and noninjection drug use practices. Subjects with HCV-specific immunity, however, were significantly more likely to have bought sex in the past 6 months, to have had more casual partners of the opposite sex in the last 6 months, and those partners were more likely to have ever injected drugs compared to subjects without HCV-specific immunity. In summary, we found serologic or cellular HCV-specific immune responses in 27.5% of NIDUs. Our results suggest that sexual behaviour associated with noninjection drug use might be a risk factor for HCV acquisition. Additional studies are needed to precisely determine the practices that lead to HCV exposure among this population.
Collapse
Affiliation(s)
- Marija Zeremski
- Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | - Jessy Makeyeva
- Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | - Kamyar Arasteh
- Baron Edmond de Rothschild Chemical Dependency Institute, Beth Israel Medical Center, New York, NY
| | - Don C. Des Jarlais
- Baron Edmond de Rothschild Chemical Dependency Institute, Beth Israel Medical Center, New York, NY
| | - Andrew H. Talal
- Center for the Study of Hepatitis C, Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| |
Collapse
|
|
50
|
|